Our data show a global shift in fibroblast phenotypes in LS skin, with Cluster 1 (CCL19/APOE), Cluster 8 (SFRP4/PRSS23), and Cluster 10 (CXADR/GATA3) more predominantly expressed in diseased skin compared with control skin, with two of the three being similar to fibroblast populations of interest reported earlier in SSc skin studies (one with a myofibroblast-like phenotype, Cluster 8), while the third (Cluster 10) appears unique to LS, and all share an upregulation of CXCR3 related chemokines CXCL9/10/11 compared with healthy controls. Here, APOE is linked to systemic sclerosis.